19-14566943-G-C

Position:

• chr19-14566943-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000215565.3(NDUFB7):​c.113-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NDUFB7 ENST00000215565.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0380

Genes affected

NDUFB7 (HGNC:7702): (NADH:ubiquinone oxidoreductase subunit B7) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is composed of 45 different subunits. It is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-14566943-G-C is Pathogenic according to our data. Variant chr19-14566943-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 997769.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB7	NM_004146.6	c.113-10C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000215565.3	NP_004137.2
NDUFB7	XM_011528039.4	c.-2-10C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_011526341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB7	ENST00000215565.3	c.113-10C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004146.6	ENSP00000215565	P1
NDUFB7	ENST00000593353.5	c.113-12C>G		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000473120

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 39 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 23, 2022

- -

Mitochondrial disorder due to a defect in assembly or maturation of the respiratory chain complexes Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Feb 01, 2021

Functional characterization, in a muscle biopsy and in fibroblasts, indicates that the c.113-10C>G variant in the NDUFB7 gene disrupts gene expression leading to a complex I defect. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: -1
DS_AL_spliceai		0.57		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2074094096; hg19: chr19-14677755;